Sulfonamide-substituted pyrazolopyridine compounds

ABSTRACT

This invention relates to compounds of the formula 
                         
in which R 1 , R 2 , and R 3  are as defined in the claims, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds, and to methods of using such compounds for treatment of hypertension and sexual dysfunction.

This application is a 371 of PCT/EP01/13064 filed Nov. 12, 2001.

The present invention relates to novel chemical compounds whichstimulate soluble guanylate cyclase, to the preparation thereof and tothe use thereof as medicaments, in particular as medicaments for thetreatment of cardiovascular disorders.

One of the most important cellular transmission systems in mammaliancells is cyclic guanosine monophosphate (cGMP). Together with nitricoxide (NO), which is released from the endothelium and transmitshormonal and mechanical signals, it forms the NO/cGMP system. Guanylatecyclases catalyze the biosynthesis of cGMP from guanosine triposphate(GTP). The representatives of this family disclosed to date can bedivided both according to structural features and according to the typeof ligands into two groups: the particulate guanylate cyclases which canbe stimulated by natriuretic peptides, and the soluble guanylatecyclases which can be stimulated by NO. The soluble guanylate cyclasesconsist of two subunits and very probably contain one heme perheterodimer, which is part of the regulatory site. The latter is ofcentral importance for the mechanism of activation. NO is able to bindto the iron atom of heme and thus markedly increase the activity of theenzyme. Heme-free preparations cannot, by contrast, be stimulated by NO.CO is also able to attach to the central iron atom of heme, but thestimulation by CO is distinctly less than that by NO.

Through the production of cGMP and the regulation, resulting therefrom,of phosphodiesterases, ion channels and protein kinases, guanylatecyclase plays a crucial part in various physiological processes, inparticular in the relaxation and proliferation of smooth muscle cells,in platelet aggregation and adhesion and in neuronal signaltransmission, and in disorders caused by an impairment of theaforementioned processes. Under pathophysiological conditions, theNO/cGMP system may be suppressed, which may lead for example to highblood pressure, platelet activation, increased cellular proliferation,endothelial dysfunction, atherosclerosis, angina pectoris, heartfailure, thromboses, stroke and myocardial infarction.

A possible way of treating such disorders which is independent of NO andaims at influencing the cGMP signal pathway in organisms is a promisingapproach because of the high efficiency and few side effects which areto be expected.

Compounds, such as organic nitrates, whose effect is based on NO have todate been exclusively used for the therapeutic stimulation of solubleguanylate cyclase. NO is produced by bioconversion and activates solubleguanylate cyclase by attaching to the central iron atom of heme. Besidesthe side effects, the development of tolerance is one of the crucialdisadvantages of this mode of treatment.

Some substances which directly stimulate soluble guanylate cyclase, i.e.without previous release of NO, have been described in recent years,such as, for example, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole(YC-1, Wu et al., Blood 84 (1994), 4226; Mülsch et al., Br. J.Pharmacol. 120 (1997), 681), fatty acids (Goldberg et al, J. Biol. Chem.252 (1977), 1279), diphenyliodonium hexafluorophosphate (Pettibone etal., Eur. J. Pharmacol. 116 (1985), 307), isoliquiritigenin (Yu et al.,Brit. J. Pharmacol. 114 (1995), 1587) and various substituted pyrazolederivatives (WO 98/16223).

In addition, WO 98/16507, WO 98/23619, WO 00/06567, WO 00/06568, WO00/06569 and WO 00/21954 describe pyrazolopyridine derivatives asstimulators of soluble guanylate cyclase. Also described inter alia inthese patent applications are pyrazolopyridines having a pyrimidineresidue in position 3. Compounds of this type have very high in vitroactivity in relation to stimulating soluble guanylate cyclase. However,it has emerged that these compounds have some disadvantages in respectof their in vivo properties such as, for example, their behavior in theliver, their pharmacokinetic behavior, their dose-response relation ortheir metabolic pathway.

It was therefore the object of the present invention to provide furtherpyrazolopyridine derivatives which act as stimulators of solubleguanylate cyclase but do not have the disadvantages, detailed above, ofthe compounds from the prior art.

This object is achieved according to the present invention by compoundsas claimed in claim 1. These novel pyrazolopyridine derivatives aredistinguished by having in position 3 a pyrimidine residue which has aparticular substitution pattern, namely a sulfonamide residue inposition 5 of the pyrimidine ring, and one or two amino groups inposition 4 and, where appropriate, 6 of the pyrimidine rings.

The present invention specifically relates to compounds of the formula(I)

in which

-   R¹ is H, Cl or NH₂;-   R² and R³ together with the heteroatoms to which they are bonded    form a five-to seven-membered heterocycle which may be saturated or    partially unsaturated, may optionally contain one or more other    heteroatoms from the group of N, O, S, and may optionally be    substituted;    and salts, isomers and hydrates thereof.

Preference is given according to the present invention to compounds ofthe formula (I) in which

-   R¹ is H, Cl or NH₂;-   R² and R³ together with the heteroatoms to which they are bonded    form a five- to seven-membered heterocycle which may be saturated or    partially unsaturated, may optionally contain one or more other    heteroatoms from the group of N, O, S;    and salts, isomers and hydrates thereof.

Particular preference is given in this connection to compounds of theformula (I) in which

-   R¹ is H, Cl or NH₂;-   R² and R³ together with the heteroatoms to which they are bonded    form a saturated five- to seven-membered heterocycle;    and salts, isomers and hydrates thereof.

The compounds of the invention of the general formula (I) may also be inthe form of their salts. Mention may generally be made here of saltswith organic or inorganic bases or acids.

Physiologically acceptable salts are preferred for the purposes of thepresent invention. Physiologically acceptable salts of the compoundsaccording to the invention may be salts of the substances according tothe invention with mineral acids, carboxylic acids or sulfonic acids.Particularly preferred examples are salts with hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid,naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid,tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts may likewise be metal or ammonium saltsof the compounds according to the invention having a free carboxylgroup. Particularly preferred examples are sodium, potassium, magnesiumor calcium salts, and ammonium salts derived from ammonia or organicamines such as, for example, ethylamine, di- or triethylamine, di- ortriethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine,lysine or ethylenediamine.

The compounds of the invention may exist in stereoisomeric forms whicheither are related as image and mirror image (enantiomers) or which arenot related as image and mirror image (diastereomers). The inventionrelates both to the enantiomers or diastereomers and to respectivemixtures thereof. The racemic forms can, just like the diastereomers, beseparated in a known manner, for example by chromatographic separation,into the stereoisomerically pure constituents. Double bonds present inthe compounds of the invention may be in the cis or trans configuration(Z or E form).

In addition, certain compounds may exist in tautomeric forms. This isknown to the skilled worker, and such compounds are likewise encompassedby the invention.

The compounds of the invention may additionally occur in the form oftheir hydrates, with the number of water molecules bound to the moleculedepending on the particular compound of the invention.

Unless indicated otherwise, the substituents have for the purposes ofthe present invention in general the following meaning:

Alkyl is generally a straight-chain or branched hydrocarbon radicalhaving 1 to 20 carbon atoms. Examples which may be mentioned are methyl,ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl,isohexyl, heptyl, isoheptyl, octyl and isooctyl, nonyl, decyl, dodeyl,eicosyl.

Alkylene is generally a straight-chain or branched hydrocarbon bridgehaving 1 to 20 carbon atoms. Examples which may be mentioned aremethylene, ethylene, propylene, α-methylethylene, β-methylethylene,α-ethylethylene, β-ethylethylene, butylene, α-methylpropylene,β-methylpropylene, γ-methylpropylene, α-ethylpropylene,β-ethylpropylene, γ-ethylpropylene, pentylene, hexylene, heptylene,octylene, nonylene, decylene, dodeylene and eicosylene.

Alkenyl is generally a straight-chain of branched hydrocarbon radicalhaving 2 to 20 carbon atoms and one or more, preferably having one ortwo, double bonds. Examples which may be mentioned are allyl, propenyl,isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl,isohexenyl, heptenyl, isoheptenyl, octenyl, isooctenyl.

Alkynyl is generally a straight-chain or branched hydrocarbon radicalhaving 2 to 20 carbon atoms and one or more, preferably having one ortwo, triple bonds. Examples which may be mentioned are ethynyl,2-butynyl, 2-pentynyl and 2-hexynyl.

Acyl is generally straight-chain or branched lower alkyl having 1 to 9carbon atoms which is linked via a carbonyl group. Examples which may bementioned are: acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl,butylcarbonyl and isobutylcarbonyl.

Alkoxy is generally a straight-chain or branched hydrocarbon radicalhaving 1 to 14 carbon atoms which is linked via an oxygen atom. Exampleswhich may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy, isoheptoxy,octoxy or isooctoxy. The terms “alkoxy” and “alkyloxy” are usedsynonymously.

Alkoxyalkyl is generally an alkyl radical having up to 8 carbon atomswhich is substituted by an alkoxy radical having up to 8 carbon atoms.

Alkoxycarbonyl can be represented for example by the formula

Alkyl in this case is generally a straight-chain or branched hydrocarbonradical having 1 to 13 carbon atoms. The following alkoxycarbonylradicals may be mentioned as examples: methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl orisobutoxycarbonyl.

Cycloalkyl is generally a cyclic hydrocarbon radical having 3 to 8carbon atoms. Cyclopropyl, cyclopentyl and cyclohexyl are preferred.Examples which may be mentioned are cyclopentyl, cyclohexyl, cycloheptyland cyclooctyl.

Cycloalkoxy is for the purposes of the invention an alkoxy radical whosehydrocarbon radical is a cycloalkyl radical. The cycloalkyl radicalgenerally has up to 8 carbon atoms. Examples which may be mentioned are:cyclopropyloxy and cyclohexyloxy. The terms “cycloalkoxy” and“cycloalkyloxy” are used synonymously.

Aryl is generally an aromatic radical having 6 to 10 carbon atoms.Preferred aryl radicals are phenyl and naphthyl.

Halogen is for the purposes of the invention fluorine, chlorine, bromineand iodine.

Heterocycle is for the purposes of the invention generally a saturated,unsaturated or aromatic 3- to 10-membered, for example 5- or 6-membered,heterocycle which may comprise up to 3 heteroatoms from the series S, Nand/or O and, in the case of a nitrogen atom, may also be bonded via thelatter. Examples which may be mentioned are: oxadiazolyl, thiadiazolyl,pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, furyl,pyrrolyl, pyrrolidinyl, piperazinyl, tetrahydropyranyl,tetrahydrofuranyl, 1,2,3 triazolyl, thiazolyl, oxazolyl, imidazolyl,morpholinyl or piperidyl. Thiazolyl, furyl, oxazolyl, pyrazolyl,triazolyl, pyridyl, pyrimidinyl, pyridazinyl and tetrahydropyranyl arepreferred. The term “heteroaryl” (or “hetaryl”) stands for an aromaticheterocyclic radical.

The compounds of the invention of the formula (I) can be prepared byreacting the compound of the formula (II)

-   where R¹ is as defined above;-   with a compound of the formula X-L-SO₂X-   where-   X is a leaving group which can be replaced by an amino group, such    as, for example, halogen;-   L is an alkanediyl group or an alkenediyl group having in each case    3 to 5 carbon atoms, where one or more carbon atoms may be replaced    by one or more heteroatoms from the group of N, O, S, and where the    group may optionally be substituted;    in the presence of an organic base at room temperature and    subsequently reacting with a base in an organic solvent with    heating.

The starting compound of the formula (IIa)

can be prepared by reacting the compound of the formula (III)

with the compound of the formula (IV)

in an organic solvent with heating to give a compound of the formula (V)

reacting with a reducing agent such as Raney nickel in the presence ofhydrogen in an organic solvent with heating to give a compound of theformula (VI)

and removal of the hydroxyl group by reaction with a chlorinating agentsuch as POCl₃ in the presence of an organic base with heating andsubsequently reacting with ammonium formate in the presence of acatalyst in an organic solvent.

The starting compound of the formula (IIb)

can be prepared by reacting the compound of the formula (III)

with the compound of the formula (VII)

in an organic solvent in the presence of a base with heating to give acompound of the formula (VIII)

and reacting with a reducing agent such as Raney nickel in an organicsolvent with heating.

The compound of the formula (III) can be prepared as shown in thefollowing reaction scheme:

The compound of the formula (III) can be obtained in a multistagesynthesis from the sodium salt of ethyl cyanopyruvate which is knownfrom the literature (Borsche and Manteuffel, Liebigs. Ann. Chem. 1934,512, 97). Reaction thereof with 2-fluoro-benzylhydrazine with heatingunder a protective gas atmosphere in an inert solvent such as dioxaneresults in ethyl 5-amino-1-(2-fluorobenzyl)pyrazole-3-carboxylate, whichis cyclized by reaction with dimethylaminoacrolein in acidic mediumunder a protective gas atmosphere with heating to give the correspondingpyridine derivative. This pyridine derivative ethyl1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate is convertedby a multistage sequence consisting of conversion of the ester withammonia into the corresponding amide, dehydration with a dehydratingagent such as trifluoroacetic anhydride to give the correspondingnitrile derivative, reaction of the nitrile derivative with sodiumethoxide and finally reaction with ammonium chloride into the compoundof the formula (III).

The compound of the formula (IV) can be obtained from ethyl cyanoacetateand aniline by the method of Menon R., Purushothaman E., J. Indian Chem.Soc. 74 (1997), 123.

Reaction of the compound of the formula (III) with the compound of theformula (IV) to give the compound of the formula (V) can take place byreacting these reactants preferably in equimolar amounts, whereappropriate in an organic solvent, for example an aromatic hydrocarbon,especially toluene, preferably under atmospheric pressure and stirringthe reaction solution for several hours, for example 12 hours, atelevated temperature, for example 60–130° C., preferably with thesolvent refluxing.

Reaction of the compound of the formula (V) to give the compound of theformula (VI) can take place by reaction with hydrogen in the presence ofa catalyst conventionally employed for such reactions, such as, forexample, Raney nickel, in an organic solvent conventionally employed forsuch reactions, such as, for example, dimethylformamide (DMF) (cf. alsothe statements concerning the synthesis of compound VIII), preferably byapplying from 30 to 80 bar of hydrogen, in particular 50 to 70 bar ofhydrogen, and stirring the reaction solution for several hours, forexample 24 hours, at elevated temperature, for example 50–100° C.,preferably at 50 to 80° C.

Removal of the hydroxyl group from the compound of the formula (VI) toobtain the compound of the formula (IIa) can preferably take placeaccording to the invention by a two-stage reaction. In the first stepaccording to the present invention the hydroxyl group is replaced by ahalogen group, preferably a chlorine radical. This can take place byreacting the compound of the formula (VI) with a preferably equimolaramount of a halogenating agent, in particular a chlorinating agent suchas, for example, POCl₃ in the presence of catalytic amounts of anorganic base, for example an amine, preferably N,N-dimethylaniline,where appropriate in an organic solvent conventionally employed for suchreactions, preferably under atmospheric pressure and stirring thereaction solution for several hours, for example 3 to 6 hours atelevated temperature, for example 60–130° C., preferably with thereaction solution refluxing. In the second step, the halogen radicalsuch as the chlorine radical is then removed in a conventional way knownto the skilled worker, for example by reaction with an excess, forexample a seven- to fifteen-fold excess of ammonium formate in thepresence of a catalyst conventionally employed for such reactions, suchas, for example, Pd/C in an organic solvent conventionally employed forsuch reactions, such as, for example, an alcohol, preferably methanol,and stirring the reaction solution for several hours to several days,for example 1 to 3 days, at elevated temperature, for example 50–130°C., preferably with the reaction solution refluxing.

Synthesis of the compound of the formula (VII), phenylazomalononitrile,from aniline and malononitrile by diazotization is known from theliterature (L. F. Cavalieri, J. F. Tanker, A. Bendich J. Am. Chem. Soc.1949, 71, 533).

Reaction of the compound of the formula (IIb) withphenylazomalononitrile (compound of the formula (VII) takes place in thepresence of a base. Bases which can be employed in this case are ingeneral inorganic or organic bases. These preferably include alkalimetal hydroxides such as, for example, sodium hydroxide or potassiumhydroxide, alkaline earth metal hydroxides such as, for example, bariumhydroxide, alkali metal carbonates such as sodium carbonate or potassiumcarbonate, alkaline earth metal carbonates such as calcium carbonate, oralkali metal or alkaline earth metal alcoholates such as sodium orpotassium methanolate, sodium or potassium ethanolate or potassiumtert-butoxide, or organic amines (trialkyl(C₁–C₆)amines) such astriethylamine, or heterocycles such as 1,4-diazabicyclo[2.2.2]octane(DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine,diaminopyridine, methylpiperidine or morpholine. It is also possible toemploy alkali metals such as sodium and hydrides thereof such as sodiumhydride as bases. Sodium methanolate is preferred.

Solvents suitable in this case are inert organic solvents. These includeethers such as diethyl ether or tetrahydrofuran, DME, dioxane, alcoholssuch as methanol and ethanol, halohydrocarbons such as dichloromethane,trichloromethane, tetrachloromethane, 1,2-dichloroethane,trichloroethane, tetrachloroethane, 1,2-dichloroethane ortrichloroethylene, hydrocarbons such as benzene, xylene, toluene,hexane, cyclohexane, or petroleum fractions, nitromethane,dimethylformamide, acetone, acetonitrile or hexamethylphosphorictriamide. It is likewise possible to employ mixtures of the solvents.Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethaneis particularly preferred.

The reaction is carried out by heating at temperatures between 60° C.and 110° C. and under atmospheric pressure. The reaction mixture isallowed to react for about 5–24 hours, preferably 12 to 24 hours.

The compound of the formula (IIb) is then obtained by cleavage of theazo group. Reducing agents which can be used for this purpose aremetals, in particular zinc, in the presence of mineral acids such ashydrochloric acid, Na₂SO₄, boranes or hydrogen in the presence of acatalyst. The use of hydrogen in the presence of Raney nickel ispreferred according to the invention.

The solvents which can be employed are the aforementioned solvents.Dimethylformamide (DMF) is particularly preferred in this connection.The reaction is preferably carried out with heating, for example at50–80° C., under a pressure of from 30 to 80 bar, preferably 50 to 70bar, of hydrogen. The reactants are allowed to react for about 24 hours.

The compounds of the formula (II) obtained in this way can be convertedinto the compounds of the invention of the formula (I) by reaction withan equimolar amount or preferably an excess, for example a one- tofive-fold excess, in particular a one- to three-fold excess, of asulfonyl compound of the formula X-L-SO₂X, where X is a leaving groupwhich can be replaced by an amino group, such as, for example, halogen,and L is an alkanediyl group or an alkenediyl group having in each case3 to 5 carbon atoms, where one or more carbon atoms may be replaced byone or more heteroatoms from the group of N, O, S, and where the groupmay optionally be substituted. The reaction takes place in two steps.Firstly, the compounds of the formula (II) are reacted with an equimolaramount or preferably an excess, for example a one- to five-fold excess,in particular a one- to three-fold excess, of the sulfonyl compound ofthe formula X-L-SO₂X described above in the presence of a base such asan organic amine, preferably pyridine, preferably under atmosphericpressure and stirring the reaction solution for several hours, forexample 12 hours, at room temperature. The sulfonyl compounds used inthis case and described above can be purchased or be obtained in amanner known to the skilled worker. The intermediates obtained in thisway are then dissolved in an organic solvent, an excess, for example aone- to ten-fold excess, in particular a three- to eight-fold excess, ofa base is added, and the reaction solution is reacted preferably underatmospheric pressure and stirring for several hours, for example 12hours, at elevated temperature for example 60–130° C., preferably,preferably 70–90° C. to give the compounds of the invention of theformula (I). Solvents suitable in this case are inert organic solvents.These include ethers such as diethyl ether or tetrahydrofuran, DME,dioxane, alcohols such as methanol and ethanol, halohydrocarbons such asdichloromethane, trichloromethane, tetrachloromethane,1,2-dichloroethane, trichloroethane, tetrachloroethane,1,2-dichloroethane or trichloroethylene, hydrocarbons such as benzene,xylene, toluene, hexane, cyclohexane, or petroleum fractions,nitromethane, dimethylformamide, acetone, acetonitrile orhexamethylphosphoric triamide. It is likewise possible to employmixtures of the solvents. Dimethylformamide is particularly preferred.Bases which can be employed in this case are generally inorganic ororganic bases. These preferably include alkali metal hydroxides such as,for example, sodium hydroxide or potassium hydroxide, alkaline earthmetal hydroxides such as, for example, barium hydroxide, alkali metalcarbonates such as sodium carbonate or potassium carbonate, alkalineearth metal carbonates such as calcium carbonate, or alkali metal oralkaline earth metal alcoholates such as sodium or potassiummethanolate, sodium or potassium ethanolate or potassium tert-butoxide,or organic amines (trialkyl(C₁–C₆)amines) such as triethylamine, orheterocycles such as 1,4-diazabicyclo[2.2.2]octane (DABCO),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine,methylpiperidine or morpholine. It is also possible to employ alkalimetals such as sodium and hydrides thereof such as sodium hydride asbases. Potassium carbonate is preferred.

The compounds of the invention of the general formula (I) show avaluable range of pharmacological effects which could not have beenpredicted.

The compounds of the invention of the general formula (I) lead tovasorelaxation, inhibition of platelet aggregation and to a reduction inblood pressure and to an increase in coronary blood flow. These effectsare mediated by direct stimulation of soluble guanylate cyclase and anintracellular increase in cGMP. In addition, the compounds of theinvention of the general formula (I) enhance the effect of substanceswhich increase the cGMP level, such as, for example, EDRF (endotheliumderived relaxing factor), NO donors, protoporphyrin IX, arachidonic acidor phenylhydrazine derivatives.

They can therefore be employed in medicaments for the treatment ofcardiovascular disorders such as, for example, for the treatment of highblood pressure and heart failure, stable and unstable angina pectoris,peripheral and cardiac vascular disorders, of arrhythmias, for thetreatment of thromboembolic disorders and ischemias such as myocardialinfarction, stroke, transistorily and ischemic attacks, disturbances ofperipheral blood flow, prevention of restenoses as after thrombolysistherapies, percutaneously transluminal angioplasties (PTAs),percutaneously transluminal coronary angioplasties (PTCAs), bypass andfor the treatment of arteriosclerosis, asthmatic disorders and diseasesof the urogenital system such as, for example, prostate hypertrophy,erectile dysfunction, female sexual dysfunction, osteoporosis,gastroparesis and incontinence.

The compounds of the invention of the general formula (I) are alsosuitable as active ingredients for controlling central nervous systemdiseases characterized by disturbances of the NO/cGMP system. They aresuitable in particular for eliminating cognitive deficits, for improvinglearning and memory and for treating Alzheimer's disease. They are alsosuitable for the treatment of central nervous system disorders such asstates of anxiety, tension and depression, CNS-related sexualdysfunctions and sleep disturbances, and for controlling pathologicaldisturbances of the intake of food, stimulants and addictive substances.

The active ingredients are furthermore also suitable for controllingcerebral blood flow and thus represent effective agents for controllingmigraine.

They are also suitable for the prophylaxis and control of the sequelaeof cerebral infarctions such as stroke, cerebral ischemias andcraniocerebral trauma. The compounds of the invention of the generalformula (I) can likewise be employed for controlling states of pain.

In addition, the compounds of the invention have an antiinflammatoryeffect and can therefore be employed as antiinflammatory agents.

Furthermore the invention also encompasses the combination of thecompounds of the invention of the general formula (I) with organicnitrates or NO donors.

Organic nitrates and NO donors for the purposes of the invention aregenerally substances which display their therapeutic effect via releaseof NO or NO species. Preference is given to sodium nitroprusside,nitroglycerine, isosorbide dinitrate, isosorbide mononitrate,molsidomine and SIN-1.

In addition, the invention also encompasses the combination withcompounds which inhibit the breakdown of cyclic guanosine monophosphate(cGMP). These are in particular inhibitors of phosphodiesterases 1, 2and 5; nomenclature of Beavo and Reifsnyder (1990), TiPS 11 pp. 150 to155. These inhibitors potentiate the effect of the compound of theinvention, and the desired pharmacological effect is increased.

BIOLOGICAL INVESTIGATIONS Vasorelaxant Effect In Vitro

Rabbits are stunned by a blow to the back of the neck and areexsanguinated. The aorta is removed, freed of adherent tissue, dividedinto rings 1.5 mm wide and put singly under tension in 5 ml organ bathscontaining carbogen-gassed Krebs-Henseleit solution at 37° C. with thefollowing composition (mM): NaCl: 119; KCl: 4.8; CaCl₂×2H₂O: 1;MgSO₄×7H₂O: 1.4; KH₂PO₄: 1.2; NaHCO₃: 25; glucose: 10. The force ofcontraction is detected with Statham UC2 cells, amplified and digitizedvia A/D converters (DAS-1802 HC, Keithley Instruments Munich) andrecorded in parallel on chart recorders. A contraction is generated byadding phenylephrine to the bath cumulatively in increasingconcentration. After several control cycles, the substance to beinvestigated is investigated in each further run in increasing dosage ineach case, and the height of the contraction is compared with the heightof the contraction reached in the last preceding run. The concentrationnecessary to reduce the height of the control value by 50% (IC₅₀) iscalculated from this. The standard application volume is 5 μl, and theDMSO content in the bath solution corresponds to 0.1%. The results arelisted in Table 1 below:

TABLE 1 Vasorelaxant effect in vitro Example No. IC₅₀ [nM] 1 290 3 350

Determination of the Liver Clearance In Vitro

Rats are anesthetized and heparinized, and the liver is perfused in situthrough the portal vein. Primary rat hepatocytes are then obtained exvivo from the liver using collagenase solution. 2·10⁶ hepatocytes per mlwere in each case incubated with the same concentration of the compoundto be investigated at 37° C. The decrease in the substrate to beinvestigated over time was determined bioanalytically (HPLC/UV,HPLC/fluorescence or LC/MSMS) at in each case 5 timepoints in the period0–15 min after the start of incubation. The clearance was calculatedtherefrom via the number of cells and weight of the liver.

Determination of the Plasma Clearance In Vivo

The substance to be investigated is administered intravenously assolution to rats via the tail vein. Blood is taken from the rats atfixed times and is heparinized, and plasma is obtained therefrom byconventional procedures. The substance is quantified in the plasmabioanalytically. The pharmacokinetic parameters are calculated from theplasma concentration/time courses found in this way by conventionalnon-compartmental methods used for this purpose.

The present invention includes pharmaceutical preparations which,besides non-toxic, inert pharmaceutically suitable carriers, comprisethe compounds of the invention of the general formula (I), and processfor the production of these preparations.

The active ingredient may also be present in microencapsulated form inone or more of the carriers indicated above.

The therapeutically effective compounds of the general formula (I)should be present in the abovementioned pharmaceutical preparations in aconcentration of about 0.1 to 99.5, preferably of about 0.5 to 95, % byweight of the complete mixture.

The abovementioned pharmaceutical preparations may, apart from thecompounds of the invention of the general formula (I), also compriseother active pharmaceutical ingredients.

It has generally proved advantageous both in human and in veterinarymedicine to administer the active ingredient(s) of the invention intotal amounts of about 0.01 to about 700, preferably 0.01 to 100, mg/kgof body weight per 24 hours, where appropriate in the form of aplurality of single doses, to achieve the desired results. A single dosecomprises the active ingredient(s) of the invention preferably inamounts of about 0.1 to about 80, in particular 0.1 to 30, mg/kg of bodyweight.

The present invention is described in detail below by means ofnon-restrictive preferred examples. Unless indicated elsewhere, allquantitative data relate to percentages by weight.

EXAMPLES Abbreviations

RT: room tempereature EA: ethyl acetate MCPBA: m-chloroperoxybenzoicacid BABA: n-butyl acetate/n-butanol/glacial acetic acid/phosphatebuffer pH 6 (50:9:25.15; org. phase) DMF: N,N-dimethylformamide

Mobile Phases for Thin-layer Chromatography

T1 E1: toluene-ethyl acetate (1:1) T1 EtOH1: toluene-methanol (1:1) C1E1: cyclohexane-ethyl acetate (1:1) C1 E2: cyclohexane-ethyl acetate(1:2)

Methods for Determining the HPLC Retention Times

Method A (HPLC-MS): Eluent: A = CH₃CN B = 0.6 g 30% HCl/1 H₂O Flow rate:0.6 ml/min Column oven: 50° C. Column: Symmetry C18 2.1*150 mm Gradient:Time (min) % A % B Flow rate (ml/min) 0 10 90 0.6 4 90 10 0.6 9 90 100.8 Method B (HPLC): Eluent: A = 5 ml HClO₄/l H₂O, B = CH₃CN Flow rate:0.75 ml/min L-R temperature: 30.00° C. 29.99° C. Column: Kromasil C1860*2 mm Gradient: Time (min) % A % B 0.50 98 2 4.50 10 90 6.50 10 906.70 98 2 7.50 98 2 Method C (HPLC): Eluent: A = H₃PO₄ 0.01 mol/l, B =CH₃CN Flow rate: 0.75 ml/min L-R temperature: 30.01° C. 29.98° C.Column: Kromasil C18 60*2 mm Gradient: Time (min) % A % B 0.00 90 100.50 90 10 4.50 10 90 8.00 10 90 8.50 90 10 10.00 90 10 Method D (chiralHPLC): Eluent: 50% isohexane, 50% ethanol Flow rate: 1.00 ml/minTemperature: 40° C. Column: 250*4.6 mm, packed with Chiralcel OD, 10 μm

Method E (HPLC-MS): Eluent: A = CH₃CN B = 0.3 g 30% HCl/1 H₂O Flow rate:0.9 ml/min Column oven: 50° C. Column: Symmetry C18 2.1*150 mm Gradient:Time (min) % A % B Flow rate (ml/min) 0 10 90 0.9 3 90 10 1.2 6 90 101.2

Starting Compounds I. Synthesis of1-2-fluorobenzyl)1H-pyrazolo[3,4-b]pyridine-3-carboxamidine

1A) Ethyl 5-amino-1-(2-fluorobenzyl)pyrazole-3-carboxylate

111.75 g (75 ml, 0.98 mol) of trifluoroacetic acid are added to 100 g(0.613 mol) of the sodium salt of ethyl cyanopyruvate (preparation inanalogy to Borsche and Manteuffel, Liebigs Ann. 1934, 512, 97) in 2.51of dioxane under argon with efficient stirring at room temperature, andthe mixture is stirred for 10 min, during which most of the precursordissolves. Then 85.93 g (0.613 mol) of 2-fluorobenzyl-hydrazine areadded, and the mixture is boiled overnight. After cooling, the sodiumtrifluoroacetate crystals which have separated out are filtered off withsuction and washed with dioxane, and the crude solution is reactedfurther.

1B) Ethyl 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate

The solution obtained from 1A) is mixed with 61.25 ml (60.77 g, 0.613mol) of dimethylaminoacrolein and 56.28 ml (83.88 g, 0.736 mol) oftrifluoroacetic acid and boiled under argon for 3 days. The solvent isthen evaporated in vacuo, and the residue is added to 2 l of water andextracted three times with 1 l of ethyl acetate each time. The combinedorganic phases are dried with magnesium sulfate and concentrated in arotary evaporator. Chromatography is carried out on 2.5 kg of silicagel, eluting with a toluene/toluene-ethyl acetate=4:1 gradient. Yield:91.6 g (49.9% of theory over two stages).

Melting point 85° C.

R_(f) (SiO₂, T1E1): 0.83.

1C) 1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide

10.18 g (34 mmol) of the ester obtained in example 1B) are introducedinto 150 ml of methanol saturated with ammonia at 0–10° C. Stirring atroom temperature for two days is followed by concentration in vacuo.

R_(f) (SiO₂, T1E1): 0.33.

1D) 3-Cyano-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine

36.1 g (133 mmol) of1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide from example1C) are dissolved in 330 ml of THF, and 27 g (341 mmol) of pyridine areadded. Then, over the course of 10 min, 47.76 ml (71.66 g, 341 mmol) oftrifluoroacetic anhydride are added, during which the temperature risesto 40° C. The mixture is stirred at room temperature overnight. Themixture is then poured into 1 l of water and extracted three times with0.5 l of ethyl acetate each time. The organic phase is washed withsaturated sodium bicarbonate solution and with 1 N HCl, dried with MgSO4and concentrated in a rotary evaporator.

Yield: 33.7 g (100% of theory)

Melting point 81° C.

R_(f) (SiO₂, T1E1): 0.74.

1E) Methyl (2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidate

30.37 g (562 mmol) of sodium methoxide are dissolved in 1.5 l ofmethanol, and 36.45 g (144.5 mmol) of3-cyano-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (from example 1D)are added. The solution obtained after stirring at room temperature for2 hours is employed directly for the next stage.

2F) 1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine

The solution of methyl(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidate in methanolobtained from example 1E) is mixed with 33.76 g (32.19 ml, 562 mmol) ofglacial acetic acid and 9.28 g (173 mmol) of ammonium chloride andstirred under reflux overnight. The solvent is evaporated in vacuo, theresidue is thoroughly triturated with acetone, and the precipitatedsolid is filtered off with suction.

¹H-NMR (d₆-DMSO, 200 MHz): δ=5.93 (s, 2H); 7.1–7.5 (m, 4H); 7.55 (dd,1H); 8.12 (dd, 1H); 8.30 (dd, 1H); 9.5 (bs, 4H-exchangeable) ppm.

MS (EI): m/z=270.2 (M−HCl).

II. Synthesis of6-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenyldiazenyl]-4-pyrimidinol

2.43 g (9.02 mmol) of1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide fromexample I and ethyl cyano[(E)-phenyldiazenyl]acetate (1.96 g, 9.02 mmol)were heated under reflux for 12 h. After cooling to room temperature,the precipitate which had separated out was filtered off and washedseveral times with toluene. Flash chromatography (CH₂Cl₂/ethyl acetate50:1→EA) afforded the desired product.

Yield: 2.52 g (63%)

R_(f): 0.72 (CH₂Cl₂/MeOH 20/1)

¹H-NMR: (300 MHz, D₆-DMSO), δ=5.87 (s, 2H, 2×CH₂O) 7.17 (t, 1H, Ar—H),7.25 (d, 1H, Ar—H), 7.3–7.6 (m, 6H, Ar—H, NH₂), 7.80 (d, 2H, Ar—H), 8.75(br. s, 2H, Ar—H), 9.05 (d, 1H), 10.23 (br. s, 1H), 12.1 (br. s, 1H).

LCMS: Ret. time: 3.94 min (column: Symmetry, C-18, 3.5 μm, 50×2.1 mm,flow rate 0.5 ml/min, 40° C., gradient: water (+0.1% formicacid):acetonitrile (+0.1% formic acid) at 0 min: 90:10, at 6.0 min10:90)); MS: (ESI pos.), m/z=441 ([M+H]⁺), (ESI neg.), m/z=439 ([M−H]⁻)

III. Synthesis of5,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]-pyridin-3-yl]-4-pyrimidinol

6-Amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenyldiazenyl]-4-pyrimidinol(2.52 g, 5.72 mmol) from example II and Raney Ni (50% in H₂O, 0.217 g)were dissolved in DMF and hydrogenated under 65 bar of H₂ at 62° C. for22 h. Cooling was followed by taking up in DMF, heating to 100° C. andfiltering off the catalyst. 10 ml of HCl (5 N) and H₂O (20 ml) wereadded to the mother liquor. After stirring at room temperature for 30min, the precipitate which had separated out was filtered off and washedwith H₂O.

Yield: 1.94 g (97%)

R_(f): 0.10 (CH₂Cl₂/MeOH 10/1)

¹H-NMR: (300 MHz, D₆-DMSO), δ=5.78 (s, 2H, OCH₂), 5.90 (s, 2H, NH₂),7.1–7.4 (m, 7H, Ar—H, NH₂), 8.64 (d, 1H, Ar—H), 8.85 (s, 1H, Ar—H), 11.7(br. s, 1 H, OH).

LC-MS: Retention time: 2.74 min (column: Symmetry, C-18, 3.5 μm, 50×2.1mm, flow rate 0.5 ml/min, 40° C., gradient: water (+0.1% formicacid):acetonitrile (+0.1% formic acid) at 0 min: 90:10, at 6.0 min10:90)); MS: (ESI pos.), m/z=352 ([M+H]⁺), (ESI neg.), m/z=350 ([M−H]⁻).

IV. Synthesis of6-chloro-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5-pyrimidinediamine

5,6-Diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-pyrimidinol(0.15 mg, 0.42 mmol) from example III was dissolved in POCl₃ (5 ml), andN,N-dimethylaniline (5.0 mg, 0.04 mmol), 0.1 equivalent) was added.After heating under reflux for 4 h, the excess reagent was removed invacuo. The residue was taken up in ethyl acetate and washed withsaturated aqueous NaHCO₃ solution, H₂O and saturated aqueous NaClsolution. The combined organic phases were concentrated and purified byflash chromatography (CH₂Cl₂:MeOH 40:1).

Yield: 0.12 g (77%)

R_(f): 0.60 (CH₂Cl₂/MeOH 10:1)

LCMS: Retention time: 3.70 min (column: Symmetry, C-18, 3.5 μm, 50×2.1mm, flow rate 0.5 ml/min, 40° C., gradient: water (+0.1% formicacid):acetonitrile (+0.1% formic acid) at 0 min: 90:10, at 6.0 min10:90)); MS: (ESI pos.), m/z=370 ([M+H]⁺), (ESI neg.), m/z=368 ([M−H]⁻).

V. Synthesis of2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5-pyrimidinediamine

6-Chloro-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5-pyrimidinediamine(74 mg, 0.20 mmol) from example V was dissolved in MeOH (4 ml), and Pd/C(10%, 20 mg) and ammonium formate (126 mg, 2.00 mmol, 10 equivalents)were added. The mixture was heated under reflux for 2 days and thenallowed to cool to room temperature before the catalyst was filteredoff. Purification took place by preparative HPLC (column: Cromsil 120ODS, C-18, 10 μm, 250×30 mm, flow rate 50 ml/min, room temperature,gradient: water acetonitrile at 0 min: 90:10, at 28 min 5:95) affordedthe desired product.

Yield: 0.054 g (80%)

R_(f): 0.10 (CH₂Cl₂/MeOH 20:1)

¹H-NMR: (300 MHz, D₆-DMSO), δ=5.90 (s, 2H, OCH₂), 7.1–7.6 (m, 6H, Ar—H),8.75 (d, 1H, Ar—H), 8.98 (d, 1H, Ar—H).

LCMS: Ret. time: 2.66 min (column: Symmetry, C-18, 3.5 μm, 50×2.1 mm,flow rate 0.5 ml/min, 40° C., gradient: water (+0.1% formicacid):acetonitrile (+0.1% formic acid) at 0 min: 90:10, at 6.0 min10:90)); MS: (ESI pos.), m/z=336 ([M+H]⁺), (ESI neg.), m/z=334 ([M−H]⁻).

VI. Synthesis of2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-phenyldiazenyl]-4,6-pyrimidinediamine

3.87 g of sodium methanolate and then 12.2 g (71.7 mmol) ofphenylazomalonitrile (L. F. Cavalieri, J. F. Tanker, A. Bendich J. Am.Chem. Soc. 1949, 71, 533) are added to a stirred solution of 21.92 g(71.1 mmol) of1-(2-fluorobenzyl)1H-pyrazolo[3,4-b]pyridine-3-carboxamidine in toluenefrom example I. The mixture is stirred at 110° C. overnight and allowedto cool. The solid which precipitates thereby is filtered off withsuction and washed with ethanol. Drying results in 23 g (73% of theory)of the desired compound.

R_(f): 0.50 (toluene/EA 1:1)

¹H-NMR: (300 MHz, D₆-DMSO), δ=5.88 (s, 2H, OCH₂), 7.1–7.5 (m, 7H, Ar—H),7.87 (br. s, 2H, NH₂), 7.96 (s, 2H, Ar—H), 8.00 (s, 1H, Ar—H), 8.03 (s,1H, Ar—H), 8.48 (br. s, 2H, NH₂), 8.65 (d, 1H, Ar—H), 9.20 (d, 1H,Ar—H).

MS: (ESI pos.), m/z=440 ([M+H]⁺).

VII. Synthesis of2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriaminetrihydrochloride

5 g (11.38 mmol) of2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)phenyldiazenyl]-4,6-pyrimidinediaminefrom example VI are hydrogenated with 800 mg of 50 percent Raney nickelin water in 60 ml of DMF under a pressure of 65 bar of hydrogen and at62° C. for 22 hours. The catalyst is filtered off with suction throughkieselguhr, and the solution is evaporated in vacuo and stirred with 5 NHCl. The yellow-brown precipitate which has separated out is filteredoff with suction and dried. 3.1 g (59.3% of theory) of the desiredcompound are obtained. The free base is obtained by shaking with diluteNaHCO₃ solution and extracted with ethyl acetate. The solid which isinsoluble in both phases is filtered off with suction. The ethyl acetatephase also contains small amounts of free base.

R_(f): 0.18 (EA)

¹H-NMR: (300 MHz, D₆-DMSO), δ=4.45 (br. s, 6H, NH₂), 5.92 (s, 2H, OCH₂),7.1–7.6 (m, 5H, Ar—H), 8.76 (d, 2H, Ar—H), 8.98 (d, 1H, Ar—H).

VIII.6-Amino-5-(1,1-dioxido-2-isothiazolidinyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-pyrimidinol

5,6-Diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-pyrimidinol(0.25 g, 0.71 mmol) from example III was introduced into pyridine (2.5ml), and 3-chloropropanesulfonyl chloride (0.19 g, 1.1 mmol, 1.5equivalents) was added. After 12 h at room temperature, the mixture wasconcentrated in vacuo and dissolved in DMF (2.5 ml). After addition ofK₂CO₃ (0.69 g, 5.0 mmol, 7 equivalents), the mixture was stirred at 40°C. for 20 h. It was taken up in ethyl acetate and H₂O and extractedseveral times with ethyl acetate. The combined organic phases were driedover Na₂SO₄ and concentrated in vacuo. The crystals obtained in this waywere stirred with CH₃CN, filtered off with suction and dried in vacuo.

Yield: 0.128 g (39%)

¹H-NMR: (300 MHz, D₆-DMSO), δ=2.43 (br. s, 2H, CH₂), 3.29 (br. s, 2H,CH₂), 3.60 (br. d, 2H, CH₂), 5.82 (s, CH₂O), 6.8 (br. s, 2H, NH₂),7.1–7.5 (m, 5H, Ar—H), 8.45 (s, 1H, Ar—H), 8.69 (d, 1H, Ar—H), 8.90 (d,1H, Ar—H), 11.93 (s, 1H, OH).

LCMS: Retention time: 3.36 min (column: Symmetry, C-18, 3.5 μm, 50×2.1mm, flow rate 0.5 ml/min, 40° C., gradient: water (+0.1% formicacid):acetonitrile (+0.1% formic acid) at 0 min: 90:10, at 6.0 min10:90));

MS: (ESI pos.), m/z=456 ([M+H]⁺), (ESI neg.), m/z=4.54 ([M+H]⁻)

EXAMPLES

1.6-Chloro-5-(1,1-dioxido-2-isothiazolidinyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-pyrimidinediamine

6-Amino-5-(1,1-dioxido-2-isothiazolidinyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-pyrimidinol(0.080 g, 0.18 mmol) from example VIII and dichlorophenylphosphine oxide(2.0 ml) were stirred at 160° C. for 2 h. Cooling was followed byhydrolysis with ice-water and purification of the crude product bypreparative HPLC (column: Cromsil 120 ODS, C-18, 10 μm, 250×30 mm, flowrate 50 ml/min, room temp., gradient: water acetonitrile at 0 min:90:10, at 28 min 5:95).

Yield: 0.050 g (60%)

¹H-NMR: (300 MHz, D₆-DMSO), δ=2.55 (t, 2H, CH₂), partly overlapped byDMSO, 3.36 (t, 2H, CH₂), partly overlapped by H₂O, 3.64 (tt, 2H, CH₂),5.84 (s, CH₂O), 7.1–7.5 (m, 5H, Ar—H), 7.9 (br. s, 2H, NH₂), 8.66 (dd,1H, Ar—H), 8.91 (d, 1H, Ar—H).

LCMS: Ret. time: 3.90 min (column: Symmetry, C-18, 3.5 μm, 50×2.1 mm,flow rate 0.5 ml/min, 40° C., gradient: water (+0.1% formicacid):acetonitrile (+0.1% formic acid) at 0 min: 90:10, at 6.0 min10:90)); MS: (ESI pos.), m/z=474 ([M+H]⁺), (ESI neg.), m/z=472 ([M+H]⁻)

2.5-(1,1-Dioxido-2-isothiazolidinyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-pyrimidinediamine

3-Chloropropanesulfonyl chloride (79 mg, 0.45 mmol, 3 equivalents) wasadded to2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5-pyrimidinediamine(50 mg, 0.15 mmol) from example V in pyridine (1.3 ml) at roomtemperature. The mixture was stirred at room temperature for 12 h andfurther 3-chloropropanesulfonyl chloride (39 mg, 0.23 mmol, 1.5equivalents) was added. After 6 h, excess reagent was removed in vacuo,and the product was purified by flash chromatography (CH₂Cl₂:MeOH 20:1).The intermediate obtained in this way was taken up in DMF (1 ml) and,after addition of K₂CO₃ (144 mg, 1.04 mmol, 7 equivalents), heated at80° C. for 12 h. DMF was then removed in vacuo, and the product waspurified by flash chromatography (CH₂Cl₂:MeOH 20:1).

Yield: 0.021 g (32%)

R_(f): 0.45 (CH₂Cl₂/MeOH 20:1)

¹H-NMR: (300 MHz, D₆-DMSO), δ=2.60 (tt, 2H, CH₂), 3.41 (t, 2H, CH₂),3.75 (t, 2H, CH₂), 5.70 (br. s, 2H, NH₂), 5.94 (s, CH₂O), 6.9–7.4 (m,5H, Ar—H, NH₂), 8.45 (s, 1H, Ar—H), 8.60 (d, 1H, Ar—H), 8.91 (d, 1H,Ar—H).

LCMS: Ret. time: 3.10 min (column: Symmetry, C-18, 3.5 μm, 50×2.1 mm,flow rate 0.5 ml/min, 40° C., gradient: water (+0.1% formicacid):acetonitrile (+0.1% formic acid) at 0 min: 90:10, at 6.0 min10:90)); MS: (ESI pos.), m/z=440 ([M+H]⁺), (ESI neg.), m/z=438 ([M+H]⁻).

Alternatively,5-(1,1-dioxido-2-isothiazolidinyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-pyrimidinylamine(example 2) was prepared from6-chloro-5(1,1-dioxido-2-isothiazolidinyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3yl]-4-pyrimidineamine(0.040 mg, 0.084 mmol) from example 1, which was dissolved in MeOH (4ml) and to which Pd/C (10%, 0.009 g) and ammonium formate (0.053 mg,0.84 mmol, 10 equivalents) were added. The mixture was heated underreflux for 2 days and then allowed to cool to room temperature, beforethe catalyst was filtered off. The crude product was concentrated invacuo.

Yield: 0.007 g (19%).

The spectroscopic data were identical to the product prepared by theroute described previously.

3.5-(1,1-Dioxido-2-isothiazolidinyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,6-pyrimidineamine

2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine(0.30 g, 0.86 mmol) from example VII was dissolved in pyridine (2 ml) atroom temperature, and 3-chloropropanesulfonyl chloride (0.23 g, 1.3mmol, 1.5 equivalents) was added. After stirring at room temperature for12 h, the solvent was removed in a rotary evaporator. The crude productobtained in this way was dissolved in DMF (1 ml), and K₂CO₃ (0.83 g, 6.0mmol, 7 equivalents) was added. The mixture was stirred at 80° C. for 12h. The crude mixture was purified by preparative HPLC (column: Cromsil120 ODS, C-18, 10 μm, 250×30 mm, flow rate 50 ml/min, room temp.,gradient: water acetonitrile at 0 min: 90:10, at 28 min 5:95).

Yield: 0.22 g (55%)

R_(f): 0.25 (CH₂Cl₂/MeOH 20:1)

¹H-NMR: (300 MHz, D₆-DMSO), δ=2.45 (tt, 2H, CH₂, partly overlapped byDMSO), 3.46 (t, 2H, CH₂), partly overlapped by 3.50 (t, 2H, CH₂), 5.81(s, CH₂O), 6.6 (br. s, 4H, 2×NH₂), 7.1–7.4 (m, 5H, Ar—H), 8.62 (m_(c),1H, Ar—H), 9.03 (d, 1H, Ar—H).

LCMS: Ret. time: 2.80 min (column: Symmetry, C-18, 3.5 μm, 50×2.1 mm,flow rate 0.5 ml/min, 40° C., gradient: water (+0.1% formicacid):acetonitrile (+0.1% formic acid) at 0 min: 90:10, at 6.0 min10:90)); MS: (ESI pos.) m/z=455 ([M+H]⁺), (ESI neg.), m/z=499 ([M+H,+HCOOH]⁻).

4.5-(1,1-Dioxido-1,2-thiazinan-2-yl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,6-pyrimidineamine

2-[1-(2-Fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine(0.080 g, 0.23 mmol) from example VII was dissolved in pyridine (5 ml)at room temperature, and 4-chlorobutanesulfonyl chloride (0.065 g, 0.34mmol, 1.5 equivalents; preparation from tetrahydrothiophene as describedby Runge et al., J. Prakt. Chem. 1955, 279, 288) was added. Afterstirring at room temperature for 12 h, the solvent was removed in arotary evaporator. The crude product obtained in this way was dissolvedin DMF (1 ml), and K₂CO₃ (0.22 g, 1.6 mmol, 7 equivalents) was added.The mixture was stirred at 80° C. for 12 h. The crude mixture waspurified by preparative HPLC (column: Cromsil 120 ODS, C-18, 10 μm,250×30 mm, flow rate 50 ml/min, room temp., gradient: water acetonitrileat 0 min: 90:10, at 28 min 5:95).

Yield: 0.022 g (19%)

R_(f): 0.25 (CH₂Cl₂/MeOH 20:1)

¹H-NMR: (300 MHz, D₆-DMSO), δ=1.90 (m_(c), 2H, CH₂), 2.15 (m_(c), 2H,CH₂), 3.48 (m_(c), 4H, 2×CH₂), 5.80 (s, CH₂O), 6.48 (br. s, 4H, 2×NH₂),7.1–7.4 (m, 5H, Ar—H), 8.61 (m_(c), 1H, Ar—H), 9.05 (d, 1H, Ar—H).

LCMS: Retention time: 2.90 min (column: Symmetry, C-18, 3.5 μm, 50×2.1mm, flow rate 0.5 ml/min, 40° C., gradient: water (+0.1% formicacid):acetonitrile (+0.1% formic acid) at 0 min: 90:10, at 6.0 min10:90)); MS: (ESI pos.), m/z=469 ([M+H]⁺).

1. A compound of the formula (I)

in which R¹ is H, Cl or NH₂; and R² and R³ together with the heteroatomsto which they are bonded form a five- to seven-membered heterocyclewhich may be saturated or partially unsaturated, may optionally containone or more other heteroatoms from the group of N, O, S, and mayoptionally be substituted; or a salt, stereoisomer or hydrates thereof.2. A compound as claimed in claim 1, in which R¹ is H, Cl or NH₂; and R²and R³ together with the heteroatoms to which they are bonded form afive- to seven-membered heterocycle which may be saturated or partiallyunsaturated, and may optionally contain one or more other heteroatomschosen from the group of N, O, S; or a salt, stereoisomer or hydratesthereof.
 3. A compound as claimed in claim 1, in which R¹ is H, Cl orNH₂; and R² and R³ together with the heteroatoms to which they arebonded form a saturated five- to seven-membered heterocycle; or a salt,stereoisomer or hydrates thereof.
 4. A process for preparing compoundsof the formula I,

wherein R¹, R², and R³are as defined above in claim 1, comprisingreaction of a compound of the formula (II)

where R¹ is as definded above in claim 1; with a compound of the formulaX-L-SO₂X where X is a leaving group which can be replaced by an aminogroup, L is an alkanediyl group or an alkenediyl group having in eachcase 3 to 5 carbon atoms, where one or more carbon atoms may be replacedby one or more heteroatoms chosen from N, O, and S, and where the groupmay optionally be substituted; in the presence of an organic base atroom temperature and subsequent reaction with a base in an organicsolvent with heating.
 5. The process of claim 4 wherein in the formulaX-L-SO₂X, the group X is Cl.
 6. A pharmaceutical composition comprisingat least one compound of the formula (I) as defined in claim
 1. 7. Apharmaceutical composition comprising at least one compound of theformula (I) as defined in claim 1 in combination with at least oneorganic nitrate or NO donor.
 8. A pharmaceutical composition comprisingat least one compound of the formula (I) as defined in claim 1 incombination with at least one compound which inhibits the breakdown ofcyclic guanosine monophosphate (cGMP).
 9. A method for the treatment ofhypertension comprising administering an effective amount of a compoundof formula (I) as defined in claim
 1. 10. A method for the treatment ofsexual dysfunction comprising administering an effective amount of acompound of formula (I) as defined in claim
 1. 11. The method as definedin claim 9 or 10, where the compound of the general formula (I) asclaimed in claim 1 is employed in combination with at least one organicnitrate or NO donor or in combination with at least one compound whichinhibits the breakdown of cyclic guanosine monophosphate (cGMP).